Substituted diaminopyrimidines

ABSTRACT

The invention relates to substituted diaminopyrimidine compounds, which are effective therapeutic compounds for treating diseases and disorders associated with those commonly treated by Protein Kinase C theta (PKCθ) inhibitors.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The inventive subject matter relates to substituted diaminopyrimidinecompounds, which are effective therapeutic compounds for treatingdiseases and disorders associated with those commonly treated by ProteinKinase C theta (PKCθ) inhibitors.

2. Description of Related Art

In International Patent Application WO 99/65881, 6-membered heterocycliccompounds are disclosed which are said to be useful as hypoglycemicagents. International Patent Application WO 00/39108 discloses aromaticheterocyclic compounds, which are said to be useful as thrombin orfactor Xa inhibitors. In International Patent Application WO 00/39101,pyrimidine compounds are disclosed which are said to be useful asanti-cancer agents. International Patent Application WO 01/00214discloses pyrimidines, which are said to be useful as SRC kinaseinhibitor compounds. In U.S. Pat. No. 6,159,982 2,4-diaminopyrimidinederivates are described as dopamine D4 receptor antagonists.

BRIEF SUMMARY OF THE INVENTION

It has now been found that the compounds of the formula 1, which aredescribed in more detail below, possess surprising and particularlyadvantageous properties.

One embodiment of the inventive subject matter relates to compounds ofthe formula 1,

in which

-   R1 is a mono- or bicyclic aromatic radical substituted by R11, R12,    R13 and R14, wherein R1 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    where    -   R11 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, or together        with R12 methylenedioxy or ethylenedioxy,    -   R12 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl, or together with R11        methylenedioxy or ethylenedioxy,    -   R13 is hydrogen, 1-4C-alkyl or halogen and    -   R14 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R2 is a mono- or bicyclic aromatic radical substituted by R21, R22,    R23 and R24, wherein R2 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    -   where    -   R21 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, or together        with R22 methylenedioxy or ethylenedioxy,    -   R22 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl, or together with R21        methylenedioxy or ethylenedioxy,    -   R23 is hydrogen, 1-4C-alkyl or halogen and    -   R24 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R3 is a mono- or bicyclic aromatic radical substituted by R31, R32,    R33 and R34, wherein R3 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    -   where    -   R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, or together        with R32 methylenedioxy or ethylenedioxy,    -   R32 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl, or together with R31        methylenedioxy or ethylenedioxy,    -   R33 is hydrogen, 1-4C-alkyl or halogen and    -   R34 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R4 is hydrogen or methyl,-   R5 is hydrogen or methyl,-   A1 is 1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—) and-   A2 is 1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—),    and their salts.

Another embodiment of the inventive subject matter relates to apharmaceutical composition comprising a compound of the above formulaand/or a pharmaceutically acceptable salt thereof together withpharmaceutically acceptable excipients and/or carrier.

A further embodiment of the inventive subject matter relates to a methodof treating a patient afflicted with a disease or disorder, comprisingthe step of administering a therapeutically effective amount of acompound as described above and/or a pharmaceutically acceptable saltthereof to said patient afflicted with said disease or disorder, whereinthe disease is selected from the group of acute and/or chronic airwaydisorders, inflammatory or allergen-induced airway disorder, bronchitis,obstructive bronchitis, spastic bronchitis, allergic bronchitis,allergic asthma, bronchial asthma, emphysema, chronic obstructivepulmonary disease (COPD), a disorder which is based on an excessiverelease of T-Cell derived cytokines, HIV-infection, septic shock, adultrespiratory distress syndrome, graft-versus-host reactions, acute orchronic rejection of organ or tissue allo- or xenografts, generalizedinflammations in the gastrointestinal area, rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, allergic and/or chronic, faultyimmunological reactions in the area of the upper airways and theadjacent regions, dermatose of the proliferative, inflammatory orallergic type, psoriasis (vulgaris), toxic and allergic contact eczema,atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus inthe anogenital area, alopecia areata, hypertrophic scars, discoid lupuserythematosus, follicular and vide-area pyodermias, endogenous andexogenous acne, acne rosacea, other proliferative, inflammatory,allergic skin disorders, a disorder in connection with disturbances ofbrain metabolism or alternatively disorders of the central nervoussystem (CNS), cerebral senility, senile dementia, multiinfarct dementia,depression, arteriosclerotic dementia, cancer and diabetes insipidus.

A still further embodiment of the inventive subject matter relates to aprocess for preparing a compound of formula 1 as described above or asalt thereof, which comprises reacting a boronic acid derivativeR1-B(OH)₂ wherein R1 has the meaning specified above, with a pyrimidinederivate of formula (4)

in which A1, A2, R2, R3, R4 and R5 have a meaning specified above, andoptionally converting an obtained compound into a corresponding salt orconverting an obtained salt into a corresponding free compound.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following terms are used herein to have the indicated meanings andare capable of including additional components well known to one ofordinary skill in the art.

1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methylradical.

Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl radicals, whichare substituted by a hydroxy group. Examples which may be mentioned arethe hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl radical.

1-4C-Alkoxy represents radicals, which in addition to the oxygen atomcontain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radical.

2-4C-Alkenyl represents straight-chain or branched alkenyl radicalshaving 2 to 4 carbon atoms. Examples which may be mentioned are the2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl radical (allylradical).

2-4C-Alkenyloxy represents a radical, which in addition to the oxygenatom contains a 2-4C-alkenyl radical. An example which may be mentionedis the allyloxy radical.

1-4C-Alkylcarbonyl represents a radical, which in addition to thecarbonyl group contains one of the aforementioned 1-4C-alkyl radicals.An example which may be mentioned is the acetyl radical.

Carboxyl is the group —COOH.

Aminocarbonyl is Amino (—NH₂) which is bound to the carbonyl group, i.e.aminocarbonyl is —CO—NH₂. Mono- or di-1-4C-alkylamino radicals contain,in addition to the nitrogen atom, one or two of the aforementioned1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred and here, inparticular, dimethyl-, diethyl or diisopropylamino.

Mono- or di-1-4C-alkylaminocarbonyl represents a radical, which inaddition to the carbonyl group contains one of the aforementioned mono-or di-1-4C-alkylamino radicals.

1-4C-Alkoxycarbonyl represents a carbonyl group, to which one of theaforementioned 1-4C-alkoxy radicals is bonded. Examples which may bementioned are the methoxycarbonyl (CH₃O—C(O)—) and the ethoxycarbonylradical (CH₃CH₂O—C(O)—).

Carboxy-1-4C-alkyl for example represents the carboxymethyl (—CH₂COOH)or the carboxyethyl radical (—CH₂CH₂COOH).

1-4C-Alkoxycarbonyl-1-4C-alkyl represents one of the aforementioned1-4C-alkyl radicals, which is substituted by one of the aforementioned1-4C-alkoxycarbonyl radicals. An example which may be mentioned is theethoxycarbonylmethyl radical (CH₃CH₂OC(O)CH₂—).

Halogen within the meaning of the invention is bromo, chloro and fluoro.

Aryl-1-4C-alkyl represents an aryl-substituted 1-4C-alkyl radical. Anexample which may be mentioned is the benzyl radical.

Aryl-1-4C-alkoxy represents an aryl-substituted 1-4C-alkoxy radical. Anexample which may be mentioned is the benzyloxy radical.

1-4C-Alkylcarbonylamino represents an amino group to which a1-4C-alkylcarbonyl radical is bonded. Examples which may be mentionedare the propionylamino (C₃H₇C(O)NH—) and the acetylamino radical(acetamido radical) (CH₃C(O)NH—).

1-4C-Alkoxycarbonylamino represents an amino radical, which issubstituted by one of the aforementioned 1-4C-alkoxycarbonyl radicals.Examples which may be mentioned are the ethoxycarbonylamino and themethoxycarbonylamino radical.

1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxyradicals, which is substituted by a further 1-4C-alkoxy radical.Examples which may be mentioned are the radicals 2-(methoxy)ethoxy(CH₃—O—CH₂—CH₂—O—) and 2-(ethoxy)ethoxy (CH₃—CH₂—O—CH₂—CH₂—O—).

1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to whichone of the aforementioned 1-4C-alkoxy-1-4C-alkoxy radicals is bonded.Examples which may be mentioned are the 2-(methoxy)-ethoxycarbonyl(CH₃—O—CH₂CH₂—O—CO—) and the 2-(ethoxy)ethoxycarbonyl radical(CH₃CH₂—O—CH₂CH₂—O—CO—).

1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino radical, whichis substituted by one of the aforementioned1-4C-alkoxy-1-4C-alkoxycarbonyl radicals. Examples which may bementioned are the 2-(methoxy)ethoxycarbonylamino and the2-(ethoxy)ethoxycarbonylamino radical.

In case that R11 together with R12, or R21 together with R22, or R31together with R32 form a methylenedioxy (—O—CH₂—O—) or ethylenedioxy(—O—CH₂CH₂—O—) group, it is necessary that R11 and R12, or R21 and R22,or R31 and R32 are in adjacent positions to each other (ortho-position).

1-3C-Alkylene represents straight-chain or branched 1-3C-alkyleneradicals, for example the methylene (—CH₂—), ethylene (—CH₂CH₂—),ethylidene [—CH(CH₃)—], trimethylene (—CH₂CH₂CH₂—), isopropylidene[—C(CH₃)₂—] and the 1-methylethylene [—CH(CH₃)—CH₂ ] radical.

The compounds according to the invention have valuable pharmacologicalproperties, which make them commercially utilizable. In one possiblemode of action they may act as selective Protein Kinase C theta (PKCθ)inhibitors. As such they are suitable as therapeutics especially for thetreatment of disorders, in particular of inflammatory nature, e.g. ofthe airways (asthma prophylaxis), of the skin, of the central nervoussystem, of the intestine, of the eyes and of the joints, which aremediated by T-cells and derived mediators such as cytokines,interleukins, chemokines, alpha-, beta- and gamma-interferon or tumornecrosis factor (TNF). The compounds according to the invention aredistinguished here by low toxicity, good enteral absorption (highbioavailability), a large therapeutic breadth and the absence ofsignificant side-effects.

On account of their PKC-inhibiting properties, the compounds accordingto the invention can be employed in human and veterinary medicine andtherapeutics, where they can be used, for example, for the treatment andprophylaxis of the following illnesses: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of various origins(bronchitis, obstructive bronchitis, spastic bronchitis, allergicbronchitis, allergic asthma, bronchial asthma, emphysema, COPD);dermatoses (especially of proliferative, inflammatory and allergic type)such as, for example, psoriasis (vulgaris), toxic and allergic contacteczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn,pruritus in the anogenital area, alopecia areata, hypertrophic scars,discoid lupus erythematosus, follicular and wide-area pyodermias,endogenous and exogenous acne, acne rosacea and other proliferative,inflammatory and allergic skin disorders; disorders which are based onan excessive release of T-cell derived cytokines, e.g. disorders of thearthritis type (rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis and other arthritic conditions), disorders of the immunesystem (AIDS, multiple sclerosis), HIV-infection, septic shock or adultrespiratory distress syndrome, graft-versus-host reactions, acute orchronic rejection of organ or tissue allo- or xenografts, andgeneralized inflammations in the gastrointestinal area (Crohn's diseaseand ulcerative colitis); disorders which are based on allergic and/orchronic, faulty immunological reactions in the area of the upper airways(pharynx, nose) and the adjacent regions (paranasal sinuses, eyes), suchas, for example, allergic rhinitis/sinusitis, chronicrhinitis/sinusitis, allergic conjunctivitis and nasal polyps autoimmunedisorders involving various tissues (e.g. kidney, pancreas, thyroidea,skin or joints). In addition, the compounds according to the inventioncan be employed for the treatment of cancer, diabetes insipidus anddisorders in connection with disturbances of brain metabolism, such as,for example, cerebral senility, senile dementia (Alzheimer's dementia),multiinfarct dementia or alternatively disorders of the CNS, such as,for example, depressions or arteriosclerotic dementia.

The compounds according to the invention may be administered as the soleactive ingredient or together, i.e. in a fixed or free combination, withother therapeutic agents used in clinical practice for the treatment ofthose diseases listed above. Reference is made in this connection toother drugs in immunomodulating regimens or other anti-inflammatoryagents e.g. for the treatment or prevention of inflammatory orautoimmune disorders or allo- or xenograft acute or chronic rejection.For example, the compounds of formula 1 may be used in combination withcyclosporines or ascomycines or their immunosuppressive analogs orderivatives; an mTOR inhibitor, corticosteroids; cyclophosphamide;azathioprene; methotrexate; an accelerating lymphocyte homing agent;leflunomide or analogs thereof, mizoribine; mycophenolic acid;mycophenolate mofetil; 15-deoxyspergualine or analogs thereof;immunosuppressive monoclonal antibodies, e.g. monoclonal antibodies toleukocyte receptors or their ligands; or other immunomodulatorycompounds, e.g. a recombinant binding molecule or portions of it e.g.CTLA4 or other adhesion molecule inhibitors, e.g. mAbs or low molecularweight inhibitors including LFA-1 antagonists, Selectin antagonists andVLA-4 antagonists. Compounds according to this invention may also beadministered together with an anti-proliferative drug, e.g. achemotherapeutic drug, e.g. in cancer treatment, or with ananti-diabetic drug in diabetes treatment.

The invention further relates to the compounds according to theinvention for use in the treatment of mammals, including man, which aresuffering from one of the abovementioned illnesses. The processcomprises administering to the sick mammal a therapeutically efficaciousand pharmacologically tolerable amount of one or more of the compoundsand/or a pharmaceutically acceptable salt thereof according to theinvention.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses, inparticular the illnesses mentioned.

The invention likewise relates to the use of the compounds according tothe invention for the production of pharmaceutical compositions whichare employed for the treatment and/or prophylaxis of the illnessesmentioned.

Pharmaceutical compositions for the treatment and/or prophylaxis of theillnesses mentioned, which contain one or more of the compoundsaccording to the invention, are furthermore a subject of the invention.

The inventive subject matter relates to compounds of the formula 1,

in which

-   R1 is a mono- or bicyclic aromatic radical substituted by R11, R12,    R13 and R14, wherein R1 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    where    -   R11 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, or together        with R12 methylenedioxy or ethylenedioxy,    -   R12 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl, or together with R11        methylenedioxy or ethylenedioxy,    -   R13 is hydrogen, 1-4C-alkyl or halogen and    -   R14 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R2 is a mono- or bicyclic aromatic radical substituted by R21, R22,    R23 and R24, wherein R2 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    -   where    -   R21 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, or together        with R22 methylenedioxy or ethylenedioxy,    -   R22 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl, or together with R21        methylenedioxy or ethylenedioxy,    -   R23 is hydrogen, 1-4C-alkyl or halogen and    -   R24 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R3 is a mono- or bicyclic aromatic radical substituted by R31, R32,    R33 and R34, wherein R3 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    -   where    -   R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, or together        with R32 methylenedioxy or ethylenedioxy,    -   R32 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl, or together with R31        methylenedioxy or ethylenedioxy,    -   R33 is hydrogen, 1-4C-alkyl or halogen and    -   R34 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R4 is hydrogen or methyl,-   R5 is hydrogen or methyl,-   A1 is 1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—) and-   A2 is 1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—),    and their salts.

Another embodiment of the Inventive subject matter relates to a compoundof formula 1,

in which

-   R1 is a mono- or bicyclic aromatic radical substituted by R11, R12,    R13 and R14, wherein R1 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    where    -   R11 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,    -   R12 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl,    -   R13 is hydrogen, 1-4C-alkyl or halogen and    -   R14 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R2 is a mono- or bicyclic aromatic radical substituted by R21, R22,    R23 and R24, wherein R2 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    -   where    -   R21 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,    -   R22 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl,    -   R23 is hydrogen, 1-4C-alkyl or halogen and    -   R24 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R3 is a mono- or bicyclic aromatic radical substituted by R31, R32,    R33 and R34, wherein R3 is selected from the group consisting of    phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl),    thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    -   where    -   R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,    -   R32 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl,    -   R33 is hydrogen, 1-4C-alkyl or halogen and    -   R34 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        substituents selected from the group consisting of 1-4C-alkyl,        1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and        mixtures thereof,-   R4 is hydrogen,-   R5 is hydrogen,-   A1 denotes 1-3C-alkylene and-   A2 denotes 1-3C-alkylene,    and their salts.

An embodiment of the inventive subject matter, to be emphasized is acompound of formula 1,

in which

-   R1 is an aromatic radical substituted by R11, R12, R13 and R14,    wherein R1 is selected from the group consisting of phenyl, furanyl    (furyl) and thiophenyl(thienyl), where    -   R11 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, trifluoromethyl, nitro, amino, mono- or        di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,        1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino        or sulfonyl, or together with R12 methylenedioxy or        ethylenedioxy,    -   R12 is hydrogen or halogen, or together with R11 methylenedioxy        or ethylenedioxy,    -   R13 is hydrogen and    -   R14 is hydrogen,-   R2 is an aromatic radical substituted by R21, R22, R23 and R24,    wherein R2 is selected from the group consisting of pyridinyl and    pyrimidinyl,    -   where    -   R21 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,    -   R22 is hydrogen or halogen,    -   R23 is hydrogen and    -   R24 is hydrogen,-   R3 is an aromatic radical substituted by R31, R32, R33 and R34,    wherein R3 is selected from the group consisting of phenyl and    pyridinyl,    -   where    -   R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl,        mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,        carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen,        hydroxyl, trifluoromethyl, nitro, amino, mono- or        di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,        1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino        or sulfonyl,    -   R32 is hydrogen or halogen,    -   R33 is hydrogen and    -   R34 is hydrogen,-   R4 is hydrogen or methyl,-   R5 is hydrogen or methyl,-   A1 is 1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—) and-   A2 is 1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—),    and their salts.

An embodiment of the inventive subject matter to be particularlyemphasized, is a compound of formula 1,

in which

-   R1 is an aromatic radical substituted by R11, R12, R13 and R14,    wherein R1 is selected from the group consisting of phenyl, furanyl    (furyl) and thiophenyl(thienyl),    -   where    -   R11 is hydrogen, 1-4C-alkoxy, 1-4C-alkylcarbonyl, carboxyl,        aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, halogen,        hydroxyl or mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, or together with R12 methylenedioxy or        ethylenedioxy,    -   R12 is hydrogen or halogen, or together with R11 methylenedioxy        or ethylenedioxy,    -   R13 is hydrogen and    -   R14 is hydrogen,-   R2 is an aromatic radical substituted by R21, R22, R23 and R24,    wherein R2 is selected from the group consisting of pyridinyl and    pyrimidinyl,    -   where    -   R21 is hydrogen,    -   R22 is hydrogen,    -   R23 is hydrogen and    -   R24 is hydrogen,-   R3 is an aromatic radical substituted by R31, R32, R33 and R34,    wherein R3 is selected from the group consisting of phenyl and    pyridinyl,    -   where    -   R31 is hydrogen, 1-4C-alkoxy or halogen,    -   R32 is hydrogen,    -   R33 is hydrogen and    -   R34 is hydrogen,-   R4 is hydrogen or methyl,-   R5 is hydrogen or methyl,-   A1 denotes methylene, ethylene, ethylidene [—CH(CH₃)—] or    ethyleneoxy (—CH₂—CH₂—O—) and-   A2 denotes methylene, ethylene, ethylidene [—CH(CH₃)—] or    ethyleneoxy (—CH₂—CH₂—O—),    and their salts.

Selected compounds of formula 1 are those,

in which

-   R1 is furanyl (furyl), thiophenyl(thienyl) or phenyl substituted by    R11 and R12,    -   where    -   R11 is hydrogen, 1-4C-alkoxy, carboxyl, aminocarbonyl, halogen        or di-1-4C-alkylamino and    -   R12 is hydrogen,-   R2 is pyridinyl,-   R3 is phenyl,-   R4 is hydrogen,-   R5 is hydrogen,-   A1 denotes methylene and-   A2 denotes methylene,    and their salts.

Further selected compounds of formula 1 are those,

in which

-   R1 is furanyl (furyl), thiophenyl(thienyl) or phenyl substituted by    R11 and R12,    -   where    -   R11 is hydrogen, 1-4C-alkoxy, 1-4C-alkylcarbonyl, carboxyl,        aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, halogen,        hydroxyl or mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, or together with R12 methylenedioxy or        ethylenedioxy,    -   R12 is hydrogen or halogen, or together with R11 methylenedioxy        or ethylenedioxy,-   R2 is pyridinyl,-   R3 is phenyl,-   R4 is hydrogen,-   R5 is hydrogen,-   A1 denotes methylene and-   A2 denotes methylene,    and their salts.

Exemplary substituents R1 are: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-dimethylaminophenyl,4-aminocarbonylphenyl, 4-carboxyphenyl, 3-chloro-4-fluorophenyl,3-acetylaminophenyl, benzo[1,3]dioxol-5-yl, 3-hydroxyphenyl,4-hydroxyphenyl, 4-acetylphenyl, 3-acetyl-phenyl, 4-acetylaminophenyl,4-dimethylaminocarbonyl-phenyl and 4-aminocarbonylphenyl.

In a preferred embodiment the inventive subject matter relates to acompound of formula 1, wherein R1 is furanyl (furyl),thiophenyl(thienyl) or phenyl substituted by R11 and R12, where R11 ishydrogen, 1-4C-alkoxy, carboxyl, aminocarbonyl, halogen ordi-1-4C-alkylamino and R12 is hydrogen.

In another preferred embodiment the inventive subject matter relates toa compound of formula 1, wherein R1 is 2-furanyl or 3-furanyl.

In a still preferred embodiment the inventive subject matter relates toa compound of formula 1, wherein R1 is 2-thiophenyl or 3-thiophenyl.

In another still preferred embodiment the inventive subject matterrelates to a compound of formula 1, wherein R1 is selected from thegroup of phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-dimethylaminophenyl,4-aminocarbonylphenyl, 4-carboxyphenyl, 3-chloro-4-fluorophenyl,3-acetylaminophenyl, benzo[1,3]dioxol-5-yl, 3-hydroxyphenyl,4-hydroxyphenyl, 4-acetylphenyl, 3-acetylphenyl, 4-acetylaminophenyl,4-dimethylaminocarbonyl-phenyl and 4-aminocarbonylphenyl.

Exemplary substituents R2 are: 4-pyridyl, 2-pyridyl, 3-pyridyl and4-pyrimidinyl. Amongst the pyridyl groups, the 2-pyridyl group ispreferred.

In another still preferred embodiment the inventive subject matterrelates to a compound of formula 1, wherein R2 is selected from thegroup of 4-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyrimidinyl.

Exemplary substituents A1-R2 are: 2-pyridylmethyl, 4-pyridylmethyl,3-pyridylmethyl, 4-pyrimidinylmethyl, 2-pyridyl-1-ethyl,2-pyridyl-2-ethyl, 3-pyridyl-2-ethyl, 4-pyrimidinyl-2-ethyl,2-pyridyloxy-2-ethyl and 3-pyridyloxy-2-ethyl.

In another still preferred embodiment the inventive subject matterrelates to a compound of formula 1, wherein A1-R2 is selected from thegroup of 2-pyridylmethyl, 4-pyridylmethyl, 3-pyridylmethyl,4-pyrimidinylmethyl, 2-pyridyl-1-ethyl, 2-pyridyl-2-ethyl,3-pyridyl-2-ethyl, 4-pyrimidinyl-2-ethyl, 2-pyridyloxy-2-ethyl and3-pyridyloxy-2-ethyl.

Exemplary substituents R3 are: phenyl, 4-fluorophenyl, 4-methoxyphenyl,and 4-pyridinyl.

In another still preferred embodiment the inventive subject matterrelates to a compound of formula 1, wherein R3 is selected from thegroup of phenyl, 4-fluorophenyl, 4-methoxyphenyl, and 4-pyridinyl.

Exemplary substituents A2-R3 are: benzyl, 4-fluorobenzyl,4-methoxybenzyl, phenyl-1-ethyl, phenyl-2-ethyl and phenoxy-2-ethyl.

In another still preferred embodiment the inventive subject matterrelates to a compound of formula 1, wherein A2-R3 is selected from thegroup of benzyl, 4-fluorobenzyl, 4-methoxybenzyl, phenyl-1-ethyl,phenyl-2-ethyl and phenoxy-2-ethyl.

The compounds according to the invention can be prepared as exemplarydescribed in the paragraph “Examples” which follows below, or usinganalogous process steps starting from appropriate starting compounds.The compounds according to the invention can be prepared for examplestarting from appropriate 2,4,5-trihalopyrimidines, for example from5-bromo-2,4-dichloropyrimidine, according to the following reactionscheme:

5-Bromo-2,4-dichloropyrimidine is reacted with the aminopiperidine 2 ina manner known per se. Advantageously, the reaction is carried out in aninert solvent at an appropriate temperature, such as room temperature,in the presence of a base (e.g. of an inorganic hydroxide, such assodium hydroxide, or of an inorganic carbonate, such as potassiumcarbonate, or of an organic nitrogen base, such as triethylamine) orwith an excess of compound 2. The subsequent reaction with the amineH₂N-A1-R2 is likewise carried out in the presence of an auxiliary baseor with an excess of the amine, preferably at temperatures higher thanroom temperature, e.g. between 60 and 150° C., in particular at theboiling point of the inert solvent used. The concluding reaction withthe boronic acid R1-B(OH)₂ is also carried out in a manner known per seto the person skilled in the art and familiar with the Suzuki reaction,e.g. as outlined in the Examples which follow below.

The starting compounds are known or can be prepared analogously to theknown compounds. The substances according to the invention are isolatedand purified in a manner known per se, for example, by distilling offthe solvent in vacuo and recrystallizing the residue obtained from asuitable solvent or subjecting it to one of the customary purificationmethods, such as, for example, column chromatography on suitable supportmaterial.

Salts are obtained by dissolving the free compound in a suitablesolvent, e.g. in a chlorinated hydrocarbon, such as dichloromethane orchloroform, or a low molecular weight aliphatic alcohol (ethanol,isopropanol) which contains the desired acid, or to which the desiredacid is subsequently added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted byalkalization or by acidification into the free compounds, which in turncan be converted into salts. In this way, salts pharmaceutically notacceptable can be converted into pharmaceutically acceptable salts.

Possible salts of compounds of the formula 1—depending onsubstitution—are especially all acid addition salts. Particular mentionmay be made of the pharmaceutically acceptable salts of the inorganicand organic acids customarily used in pharmacy. Those suitable arewater-soluble and water-insoluble acid addition salts with acids suchas, for example, hydrochloric acid, hydrobromic acid, phosphoric acid,nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid,benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid,sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid,toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoicacid, where the acids are used in salt preparation—depending on whethera mono- or polybasic acid is concerned and on which salt is desired—inan equimolar quantitative ratio or one differing therefrom.

Salts, which are pharmaceutically not acceptable, which can initially beobtained, for example, as process products in the production of thecompounds according to the invention on the industrial scale, areconverted into the pharmaceutically acceptable salts by processes knownto the person skilled in the art.

It is known to the person skilled in the art that the compoundsaccording to invention and their salts, if, for example, they areisolated in crystalline form, can contain various amounts of solvents.The invention therefore also comprises all solvates and in particularall hydrates of the compounds of the formula 1, and also all solvatesand in particular all hydrates of the salts of the compounds of theformula 1.

In case of A1 and/or A2 being ethylidene [—CH(CH₃)—], the compounds ofthe formula 1 have one or two chiral centers. The invention relates toall four conceivable stereoisomers in any desired mixing ratio with oneanother, including the pure enantiomers, which are a preferred subjectof the invention and which can be synthesized by using the correspondingoptically pure starting compounds.

A further subject of the invention is a commercial product, consistingof a customary secondary pack, a primary pack containing thepharmaceutical composition (for example an ampoule or a blister pack)and, if desired, a pack insert, the medicament exhibiting antagonisticaction against Protein Kinase C theta (PKCθ) and leading to theattenuation of the symptoms of illnesses which are connected ProteinKinase C theta (PKCθ), and the suitability of the medicament for theprophylaxis or treatment of illnesses which are connected with ProteinKinase C theta (PKCθ) being indicated on the secondary pack and/or onthe pack insert of the commercial product, and the medicament containingone or more compounds of the formula I according to the invention. Thesecondary pack, the primary pack containing the medicament and the packinsert otherwise comply with what would be regarded as standard to theperson skilled in the art for pharmaceutical compositions of this type.

The pharmaceutical compositions are prepared by processes, which areknown per se and familiar to the person skilled in the art Aspharmaceutical compositions, the compounds according to the invention(=active compounds) are either employed as such, or preferably incombination with suitable pharmaceutical excipients, e.g. in the form oftablets, coated tablets, capsules, suppositories, patches, emulsions,suspensions, gels or solutions, the active compound contentadvantageously being between 0.1 and 95%.

The person skilled in the art is familiar on the basis of his/her expertknowledge with the excipients, which are suitable for the desiredpharmaceutical formulations. In addition to solvents, gel-formingagents, ointment bases and other active compound vehicles, it ispossible to use, for example, antioxidants, dispersants, emulsifiers,preservatives, solubilizers or permeation promoters.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk@,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular used in the form of those pharmaceuticalcompositions, which are suitable for topical application. For theproduction of the pharmaceutical compositions, the compounds accordingto the invention (=active compounds) are preferably mixed with suitablepharmaceutical excipients and further processed to give suitablepharmaceutical formulations. Suitable pharmaceutical formulations, whichmay be mentioned are, for example, powders, emulsions, suspensions,sprays, oils, ointments, fatty ointments, creams, pastes, gels orsolutions.

Pharmaceutical compositions according to the invention can be preparedby processes known per se. Dosage of the active compounds takes place inthe order of magnitude customary for PKCθ inhibitors. Thus topicalapplication forms (such as, for example, ointments) for the treatment ofdermatoses contain the active compounds in a concentration of, forexample, 0.1-99%. The dose for administration by inhalation iscustomarily between 0.1 and 3 mg per day. The customary dose in the caseof systemic therapy (p.o. or i.v.) is between 0.03 and 3 mg per kilogramper day.

The following examples are illustrative of the present invention and arenot intended to be limitations thereon. Likewise, further compounds ofthe formula 1 whose preparation is not described explicitly can beprepared analogously or in a manner familiar to the person skilled inthe art using customary process techniques. The abbreviation ESMS standsfor Electro Spray Mass Spectroscopy and eq stands for equivalent(s).

EXAMPLES

Final Products

1.[1-Benzyl(4-piperidyl)]{2-[(2-pyridylmethyl)amino]-5-(3-thienyl)pyrimidin-4-yl}amine

3-Thiopheneboronic acid (0.62 g, 4.85 mmol) was added to a solution of{5-bromo-2-[(2-pyridylmethyl)-amino]pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine(1.00 g, 2.21 mmol) in ethylene glycol dimethyl ether (50 mL). Asolution of potassium carbonate (1.25 g, 9.04 mmol) in water (15 mL) wasadded to the above reaction mixture.Tetrakis(triphenylphosphine)palladium (260 mg, 0.225 mmol) was added tothe reaction and stirred at 80° C. under nitrogen for 2 hours. Thereaction mixture was diluted with water (150 mL) and extracted withmethylene chloride (4×100 mL). The organic layer was concentrated andthe residue was purified using flash chromatography (5% methanol inethyl acetate) to give[1-benzyl(4-piperidyl)]{2-[(2-pyridylmethyl)amino]-5-(3-thienyl)pyrimidin-4-yl}amine(0.45 g, 45% yield) as an off-white foam; ESMS 457 (M+1)⁺.

2.{5-(4-Methoxyphenyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-methoxyphenyl boronic acid as described in Example 1 as an off-whitefoam; ESMS 481 (M+1)⁺.

3.{5-Phenyl-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,phenyl boronic acid as described in Example 1 as an off-white foam; ESMS451 (M+1)⁺.

4.{5-(4-Chlorophenyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-chlorophenyl boronic acid as described in Example 1 as an off-whitefoam; ESMS 486 (M+1)⁺.

5.{5-(4-(N,N-Dimethylamino)phenyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-(N,N-dimethylamino)phenyl boronic acid as described in Example 1 as anoff-white foam; ESMS 494 (M+1)⁺.

6.{5-(Phenyl-4-carboxamido)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]-amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-carboxyphenylboronic acid as described in Example 3 to provide{5-(4-carboxyphenyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine.A solution of{5-(4-carboxy-phenyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,carbonyl diimidazole (1.2 eq), ammonium hydroxide (12 eq) intetrahydrofuran (25 mL) was stirred at room temperature for 6 h. Flashchromatography (SiO₂, 5% methanol in ethyl acetate) afforded the titlecompound as white solid; ESMS 494 (M+1)⁺.

7.{5-(4-Carboxyphenyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-carboxyphenylboronic acid as described in Example 1 to provide thetitle compound; ESMS 495 (M+1)⁺.

8.{5-(2-Thienyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from(5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine,2-thienylboronic acid as described in Example 1 to provide the titlecompound; ESMS 457 (M+1)⁺.

9.{5-(2-Furanyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,2-furanylboronic acid as described in Example 1 to provide the titlecompound; ESMS 441 (M+1)⁺.

10.{5-(3-Furanyl)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,3-furanylboronic acid as described in Example 1 to provide the titlecompound; ESMS 441 (M+1)⁺.

11.{5-(3-Thienyl)-2-[(4-pyridylmethyl)amino)pyrimidin-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,3-thienylboronic acid as described in Example 1 to provide the titlecompound; ESMS 457 (M+1)⁺.

12.{5-(2-Furanyl)-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,2-furanylboronic acid as described in Example 1 to provide the titlecompound; ESMS 441 (M+1)⁺.

13.{5-(3-Furanyl)-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,3-furanylboronic acid as described in Example 1 to provide the titlecompound; ESMS 441 (M+1)⁺.

14.{5-(2-Thienyl)-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,2-thienylboronic acid as described in Example 1 to provide the titlecompound; ESMS 457 (M+1)⁺.

15.{5-(Phenyl-4-carboxamido)-2-[2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from{5-bromo-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-carboxyphenylboronic acid as described in Example 3 to provide{5-(phenyl-4-carboxy)-2-[(2-pyridylmethyl)amino)pyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine.A solution of{5-(phenyl-4-carboxy)-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine,carbonyl diimidazole (1.2 eq), ammonium hydroxide (12 eq) intetrahydrofuran (0.1M) was stirred at room temperature for 6 h. Flashchromatography (SiO2, 5% methanol in ethyl acetate) afforded the titlecompound as white solid; ESMS 494 (M+1)⁺.

16.N(4)-(1-Benzyl-piperidin-4-yl)-5-(3-chloro-4-fluoro-phenyl)-N(2)-pyridin-2-ylmethyl-pyrimidine-2,4-diamine

The title compound was prepared from(5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,3-chloro-4-fluoro-phenyl boronic acid as described in Example 1 as anoff-white foam; ESMS 503 (M+1)⁺.

17.N-(3-[4-(1-Benzyl-piperidin-4-ylamino)-2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-5-yl]phenyl)-acetamide

The title compound was prepared from(5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine,3-acetaminophenyl boronic acid as described in Example 1 as an off-whitefoam; ESMS 508 (M+1)⁺.

18.5-Benzo[1,3]dioxol-5-yl-N(4)-(1-benzyl-piperidin-4-yl)-N(2)-pyridin-2-ylmethyl-pyrimidine-2,4-diamine

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,5-benzo[1,3]dioxolo boronic acid as described in Example 1 as anoff-white foam; ESMS 495 (M+1)⁺.

19.3-[4-(1-Benzyl-piperidin-4-ylamino)-2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-5-yl]-phenol

The title compound was prepared from(5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,3-hydroxyphenylphenyl boronic acid as described in Example 1 as anoff-white foam; ESMS 467 (M+1)⁺.

20.4-{4-(1-Benzyl-piperidin-4-ylamino)-2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-5-yl}-phenol

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-hydroxyphenyl boronic acid as described in Example 1 as an off-whitefoam; ESMS 467 (M+1)⁺.

21. 1-(4{(4-(1-Benzyl-piperidinylamino)-2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-5-yl}phenyl)-ethanone

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine,4-acetylphenyl boronic acid as described in Example 1 as an off-whitefoam; ESMS 493 (M+1)⁺.

22. 1-(3-[4-(1-Benzyl-piperidinylamino)-2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-5-yl}phenyl)-ethanone

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,3-acetylphenyl boronic acid as described in Example 1 as an off-whitefoam; ESMS 493 (M+1)⁺.

23. 4-{4-(1-Benzylpiperidin-4-ylamino)-2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-5-yl}N,N-di-methyl-benzamide

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-dimethylaminocarbonylphenyl boronic acid as described in Example 1 asan off-white foam; ESMS 522 (M+1)⁺.

24.N-(4-[4-(1-Benzyl-piperidin-4-ylamino)-2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-5-yl]-phenyl)-acetamide

The title compound was prepared from{5-bromo-2-[(4-pyridylmethyl)amino)pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine,4-acetaminophenyl boronic acid as described in Example 1 as an off-whitefoam; ESMS 508 (M+1)⁺.

Intermediates

A. (5-Bromo-2-chloropyrimidin-4-yl)[1-benzyl (4-piperidyl)]amine

4-Amino-1-benzylpiperidine (4.09 g, 0.22 mol) was added to a solution of5-bromo-2, 4-dichloropyrimidine (4.90 g, 0.22 mol) and potassiumcarbonate (3.86 g, 0.28 mol) in THF (150 mL) under constant stirring atroom temperature. The reaction was stirred for 30 min at roomtemperature then diluted with water (400 mL) and extracted with ethylacetate (2×200 mL). The organic layer was separated and evaporated underreduced pressure to give a residue. The residue was purified using flashchromatography (SiO₂, ethyl acetate) to give(5-bromo-2-chloropyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine (5.15 g,65% yield) as clear oil; ESMS 381 (M+1)⁺.

B. Ethyl 4-({5-bromo-2-chloropyrimidin-4-yl}amino)piperidinecarboxylate

The title compound was prepared from ethyl 4-aminopiperdinecarboxylateand 5-bromo-2,4-dichloro-pyrimidine as described in Example A to givethe title compound; ESMS 363 (M+1)⁺.

C.{5-Bromo-2-[(2-pyridylmethyl)amino]pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

A solution of(5-bromo-2-chloropyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine (4.91 g,0.13 mol) and 2-(aminomethyl)pyridine (3.20 g, 0.30 mol) was heated(neat) at 120° C. for 25 minutes. The reaction mixture was partitionedbetween ethyl acetate (300 mL) and saturated aqueous NaHCO₃ solution(300 mL). The organic layer was separated, washed with brine,concentrated, and purified using flash chromatography (10% methanol inethyl acetate) to give{5-bromo-2-[(2-pyridylmethyl)amino]pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine(3.18 g 55% yield) as off-white foam; ESMS 453 (M+1)⁺.

D.{5-Bromo-2-[(4-pyridylmethyl)amino]pyrimidin-4-yl}[1-benzyl(4-piperidyl)]amine

The title compound was prepared from(5-bromo-2-chloropyrimidin-4-yl)[1-benzyl(4-piperidyl)]amine and4-(aminomethyl)pyridine as described in Example C to provide anoff-white foam; ESMS 453 (M+1)⁺.

E. Ethyl4-({5-bromo-2-[(2-pyridylmethyl)amino]pyrimidin-4-yl}amino)piperdinecarboxylate

The title compound was prepared from Ethyl4-({5-bromo-2-chloropyrimidin-4-yl}amino)piperidine-carboxylate and2-(aminomethyl)pyridine as described in Example C to give the titlecompound; ESMS 453 (M+1)⁺.

Biological Investigations

Protein kinase C-theta is a member of the Ca²⁺-independent novel proteinkinase C (PKC) subfamily, which is predominantly expressed in skeletalmuscle and T-cells (Baler et al., JBC 268:4997; Bauer et al., Eur J.Immunol 30: 3645). PKC-θ was shown to selectively colocalize with theTCR to the T cell synapse when antigen-specific T cells are engaged bytheir physiological ligand (Monks et al., Nature 395:82; Monks et al.,Nature 385:83). Functional studies of PKC-θ revealed an early andessential role in the TCR/CD28-induced stimulation of MAP kinaseJNK/AP-1 and NFAT, but also the IKKβ/I-κB/NF-κB signaling cascade (seefor review Altman et al., Immunol Today 21:567; Bauer and Baier, 2002Mol. Immunol., submitted).

In T cells PKC-θ activates AP-1, NFAT and NF-κB (Bauer et al., Eur. J.Immunol. 30: 3645; Lin et al., Mol Cell Biol 20:2933; Coudronniere etal., PNAS 97:3394) and PKC-θ was shown to synergize with Calcineurin ininducing the IL-2 gene (Werlen et al., EMBO J. 17:3101; Ghaffari-Tabriziet al., Eur. J. Immunol. 29:132). Inhibition of PKC-θ leads to impairedT-cell functions (Baier-Bitterlich et al., Mol Cell Biol 16:1842;Ghaffari-Tabrizi et al., Eur. J. Immunol. 29:132). Consistently, T-cellsof PKC-θ-deficient mice display profound defects in TCR-induced IL-2production and, subsequently, T-cell proliferation (Sun et al, Nature404:402; Pfeifhofer et al., submitted).

For the investigation of PKC-θ inhibition on the enzymatic level thephosphorylation of a substrate pep-tide by recombinant PKC-θ enzyme canbe measured. On the cellular level (in vitro) the immunomodulatorypotential of PKC-θ inhibitors is evident from the inhibition ofactivated T-cell responses such as proliferation, cytokine synthesis(e.g. IL2) and expression of activation markers. Substances, whichinhibit the aforementioned proinflammatory parameters are those whichinhibit PKC-E.

Protein Kinase C-θ Assay

The compounds of formula 1 were tested for their activity on PKC-θaccording to the following method. The assay was performed in 96 wellmicrotiter plates (Perkin Elmer Wallac) at a final assay volume of 200μl. The reaction mixture (50 μl) contained 10 μl of recombinant humanPKC-θ enzyme together with 5 μl of the test compound and 3 μMbiotinylated PKC-θ substrate peptide (Biotin-RKRQRSMRRRVHOH), 160 μMphosphatidylserine, 0.3 mg/ml BSA, 1 μM ATP and 2 μCi of ³³γ-ATP(Amersham) in 40 mM Tris-buffer pH 7.4. Incubation was performed for 40min at room temperature. The reaction was stopped by adding 150 μl of amixture containing 10 mM ATP and 1.33 mg/ml streptavidin coated yttriumsilicate SPA beads (Amersham). Incorporated radioactivity (cpm) wasmeasured for 2 min in a radioactivity counter (Wallac MicroBeta JET).According to the method described above IC₅₀ measurement was performedon a routine basis by incubating a serial dilution of inhibitor at thedesired concentrations and a final DMSO concentration of 1% (v/v), whichdid not affect PKC-θ activity. IC₅₀ values for inhibition of PKC-θ werecalculated from the concentration-inhibition curves bynonlinear-regression.

The inhibitory values determined for the compounds according to theinvention follow from the following table A, in which the numbers of thecompounds correspond to the numbers of the examples. TABLE A Inhibitionof PKC-θ activity [measured as IC₅₀ (μmol/l)] Example No. PKC-θ 1 <4.012 <4.0 13 <4.0 14 <4.0 15 <4.0 16 <4.0 17 <4.0 18 <4.0 19 <4.0 20 <4.021 <4.0 22 <4.0 23 <4.0 24 <4.0

To determine the effects of compounds of formula 1 on T-cell activationthe following assays were performed.

CD4+ Proliferation Assay

CD4+ lymphocytes were purified as described by Hatzelmann and Schudt (JPharmacol Exp Ther 297: 267-279) and resuspended in assay medium (RPMI1640/10% fetal calf serum (FCS) containing 2 mM Glutamine, 1%sodiumpyruvate, 1% non-essential amino acids and 1%penicillin/streptomycin) at a density of 1×10⁶ cells/ml. 96 well plateswere coated with αCD3 antibodies (0.3 μg/well; Ortho-clone OKT-3,Jansen-Cilag) for 2.5 h at 37° C. in 5% CO₂ and then washed twice withPBS (200 μl/well). Prior to plating of the cells (200 μl, 2×10⁵ cells)the compounds of formula 1 dissolved in 2% DMSO were added to theantibody-coated plates at the desired concentrations. Following apreincubation period of 30 min at 37° C. and 5% CO₂ 10 μl of αCD28antibody (3 μg/ml, Beckman) were added and incubation continued for 48 hat 37° C. and 5% CO₂. 18 h prior to cell harvest 10 μl of³H-methylthymidin (0.2 μCi, Amersham) were added. After 48 h totalincubation time the cells were lysed using deionized water andradiolabeled DNA was immobilized on 96 well filter plates using a Tomtecdevice. The plates were dried at 60° C. for 1 h and overlayed with 40 μlMicroscint-O (Packard) before counting in a Topcount radioactivitycounter (Packard). Calculation of IC50 values was performed as describedabove.

The inhibitory values determined for the compounds according to theinvention follow from the following table B, in which the numbers of thecompounds correspond to the numbers of the examples. TABLE B Inhibitionof CD4+ cell proliferation [measured as IC₅₀ (μmol/l)] CD4+ Example No.proliferation 1 <4.0 8 <4.0 14 <4.0 15 <4.0CD4+ IL-2 Secretion Assay

CD4+ T lymphocytes were stimulated and treated with compounds of formula1 as described above for the CD4+ proliferation assay. Following a 48 hincubation period IL-2 levels in the supernatants (50 μl/well) weredetermined by ELISA (Beckman Coulter). Calculation of IC₅₀ values wasperformed as described above.

The inhibitory values on CD4+ T-cell activation determined for thecompounds according to the invention follow from the following table C,in which the numbers of the compounds correspond to the numbers of theexamples. TABLE C Inhibition of IL-2 secretion in CD4+ cell [measured asIC₅₀ (μmol/l)] CD4+ IL2 Example No. proliferation 1 <4.0 6 <4.0 8 <4.012 <4.0 13 <4.0 14 <4.0 15 <4.0The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

1. A compound of formula 1,

in which R1 is a mono- or bicyclic aromatic radical substituted by R11,R12, R13 and R14, wherein R1 is selected from the group consisting ofphenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuryl),thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl, whereR11 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, aryl,aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro,amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino orsulfonyl, or together with R12 methylenedioxy or ethylenedioxy, R12 ishydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,trifluoromethyl or hydroxyl, or together with R11 methylenedioxy orethylenedioxy, R13 is hydrogen, 1-4C-alkyl or halogen and R14 ishydrogen, 1-4C-alkyl or halogen, where aryl is phenyl or substitutedphenyl having one, two or three substituents selected from the groupconsisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl,halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano andmixtures thereof, R2 is a mono- or bicyclic aromatic radical substitutedby R21, R22, R23 and R24, wherein R2 is selected from the groupconsisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3-triazolyl, indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl), thiophenyl(thienyl), benzothiophenyl (benzothienyl),thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl andisoquinolinyl, where R21 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl,1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl,aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl,aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl,nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino orsulfonyl, or together with R22 methylenedioxy or ethylenedioxy, R22 ishydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,trifluoromethyl or hydroxyl, or together with R21 methylenedioxy orethylenedioxy, R23 is hydrogen, 1-4C-alkyl or halogen and R24 ishydrogen, 1-4C-alkyl or halogen, where aryl is phenyl or substitutedphenyl having one, two or three substituents selected from the groupconsisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl,halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano andmixtures thereof, R3 is a mono- or bicyclic aromatic radical substitutedby R31, R32, R33 and R34, wherein R3 is selected from the groupconsisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3-triazolyl, indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl), thiophenyl(thienyl), benzothiophenyl (benzothienyl),thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl andisoquinolinyl, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl,1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl,aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl,aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl,nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino orsulfonyl, or together with R32 methylenedioxy or ethylenedioxy, R32 ishydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,trifluoromethyl or hydroxyl, or together with R31 methylenedioxy orethylenedioxy, R33 is hydrogen, 1-4C-alkyl or halogen and R34 ishydrogen, 1-4C-alkyl or halogen, where aryl is phenyl or substitutedphenyl having one, two or three substituents selected from the groupconsisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl,halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano andmixtures thereof, R4 is hydrogen or methyl, R5 is hydrogen or methyl, A1is 1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—) and A2 is 1-3C-alkylene orethyleneoxy (—CH₂—CH₂—O—), or a hydrate, solvate, salt, hydrate of asalt or solvate of a salt thereof.
 2. A compound of formula 1 accordingto claim 1, in which R1 is a mono- or bicyclic aromatic radicalsubstituted by R11, R12, R13 and R14, wherein R1 is selected from thegroup consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3-triazolyl, indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl(benzofuryl), thiophenyl(thienyl), benzothiophenyl (benzothienyl),thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl andisoquinolinyl, where R11 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl,1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl,aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl,aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl,nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino orsulfonyl, R12 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,halogen, trifluoromethyl or hydroxyl, R13 is hydrogen, 1-4C-alkyl orhalogen and R14 is hydrogen, 1-4C-alkyl or halogen, where aryl is phenylor substituted phenyl having one, two or three substituents selectedfrom the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl,1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy,hydroxyl, cyano and mixtures thereof, R2 is a mono- or bicyclic aromaticradical substituted by R21, R22, R23 and R24, wherein R2 is selectedfrom the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furanyl (furyl),benzofuranyl (benzofuryl), thiophenyl(thienyl), benzothiophenyl(benzothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl,quinolinyl and isoquinolinyl, where R21 is hydrogen, 1-4C-alkyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl,carboxyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl,halogen, hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy,trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R22 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethylor hydroxyl, R23 is hydrogen, 1-4C-alkyl or halogen and R24 is hydrogen,1-4C-alkyl or halogen, where aryl is phenyl or substituted phenyl havingone, two or three substituents selected from the group consisting of1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,trifluoromethyl, nitro, trifluoromethoxy, hydroxyl, cyano and mixturesthereof, R3 is a mono- or bicyclic aromatic radical substituted by R31,R32, R33 and R34, wherein R3 is selected from the group consisting ofphenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuryl),thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl,isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl, whereR31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, aryl,aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro,amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino orsulfonyl, R32 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,halogen, trifluoromethyl or hydroxyl, R33 is hydrogen, 1-4C-alkyl orhalogen and R34 is hydrogen, 1-4C-alkyl or halogen, where aryl is phenylor substituted phenyl having one, two or three substituents selectedfrom the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl,1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy,hydroxyl, cyano and mixtures thereof, R4 is hydrogen, R5 is hydrogen, A1denotes 1-3C-alkylene and A2 denotes 1-3C-alkylene, or a hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof.
 3. Acompound of formula 1 according to claim 1, in which R1 is an aromaticradical substituted by R11, R12, R13 and R14, wherein R1 is selectedfrom the group consisting of phenyl, furanyl (furyl) and thiophenyl(thienyl), where R11 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl,1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl,aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl,carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl,trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, or together with R12methylenedioxy or ethylenedioxy, R12 is hydrogen or halogen, or togetherwith R11 methylenedioxy or ethylenedioxy, R13 is hydrogen and R14 ishydrogen, R2 is an aromatic radical substituted by R21, R22, R23 andR24, wherein R2 is selected from the group consisting of pyridinyl andpyrimidinyl, where R21 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,R22 is hydrogen or halogen, R23 is hydrogen and R24 is hydrogen, R3 isan aromatic radical substituted by R31, R32, R33 and R34, wherein R3 isselected from the group consisting of phenyl and pyridinyl, where R31 ishydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,1-4C-alkylcarbonyl, carboxyl, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, trifluoromethyl,nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino orsulfonyl, R32 is hydrogen or halogen, R33 is hydrogen and R34 ishydrogen, R4 is hydrogen or methyl, R5 is hydrogen or methyl, A1 is1-3C-alkylene or ethyleneoxy (—CH₂—CH₂—O—) and A2 is 1-3C-alkylene orethyleneoxy (—CH₂—CH₂—O—), or a hydrate, solvate, salt, hydrate of asalt or solvate of a salt thereof.
 4. A compound of formula 1 accordingto claim 1, in which R1 is an aromatic radical substituted by R11, R12,R13 and R14, wherein R1 is selected from the group consisting of phenyl,furanyl (furyl) and thiophenyl (thienyl), where R11 is hydrogen,1-4C-alkoxy, 1-4C-alkylcarbonyl, carboxyl, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, halogen, hydroxyl or mono- ordi-1-4C-alkylamino, or together with R12 methylenedioxy orethylenedioxy, R12 is hydrogen or halogen, or together with R11methylenedioxy or ethylenedioxy, R13 is hydrogen and R14 is hydrogen, R2is an aromatic radical substituted by R21, R22, R23 and R24, wherein R2is selected from the group consisting of pyridinyl and pyrimidinyl,where R21 is hydrogen, R22 is hydrogen, R23 is hydrogen and R24 ishydrogen, R3 is an aromatic radical substituted by R31, R32, R33 andR34, wherein R3 is selected from the group consisting of phenyl andpyridinyl, where R31 is hydrogen, 1-4C-alkoxy or halogen, R32 ishydrogen, R33 is hydrogen and R34 is hydrogen, R4 is hydrogen or methyl,R5 is hydrogen or methyl, A1 denotes methylene, ethylene, ethylidene[—CH(CH₃)—] or ethyleneoxy (—CH₂—CH₂—O—) and A2 denotes methylene,ethylene, ethylidene [—CH(CH₃)—] or ethyleneoxy (—CH₂—CH₂—O—), or ahydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.5. A compound of formula 1 according to claim 1, in which R1 is anaromatic radical substituted by R11, R12, R13 and R14, wherein R1 isselected from the group consisting of phenyl, furanyl (furyl) andthiophenyl (thienyl), where R11 is hydrogen, 1-4C-alkoxy,1-4C-alkylcarbonyl, carboxyl, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, halogen, hydroxyl or mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, or together with R12methylenedioxy or ethylenedioxy, R12 is hydrogen or halogen, or togetherwith R11 methylenedioxy or ethylenedioxy, R13 is hydrogen and R14 ishydrogen, R2 is an aromatic radical substituted by R21, R22, R23 andR24, wherein R2 is selected from the group consisting of pyridinyl andpyrimidinyl, where R21 is hydrogen, R22 is hydrogen, R23 is hydrogen andR24 is hydrogen, R3 is an aromatic radical substituted by R31, R32, R33and R34, wherein R3 is selected from the group consisting of phenyl andpyridinyl, where R31 is hydrogen, 1-4C-alkoxy or halogen, R32 ishydrogen, R33 is hydrogen and R34 is hydrogen, R4 is hydrogen or methyl,R5 is hydrogen or methyl, A1 denotes methylene, ethylene, ethylidene(—CH(CH₃)—] or ethyleneoxy (—CH₂—CH₂—O—) and A2 denotes methylene,ethylene, ethylidene [—CH(CH₃)—] or ethyleneoxy (—CH₂—CH₂—O—), or ahydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.6. A compound of formula 1 according to claim 1, in which R1 is furanyl(furyl), thiophenyl(thienyl) or phenyl substituted by R11 and R12, whereR11 is hydrogen, 1-4C-alkoxy, 1-4C-alkylcarbonyl, carboxyl,aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, halogen, hydroxyl ormono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, or together withR12 methylenedioxy or ethylenedioxy, R12 is hydrogen or halogen, ortogether with R11 methylenedioxy or ethylenedioxy, R2 is pyridinyl, R3is phenyl, R4 is hydrogen, R5 is hydrogen, A1 denotes methylene and A2denotes methylene, or a hydrate, solvate, salt, hydrate of a salt orsolvate of a salt thereof.
 7. A compound of formula 1 according to claim1, in which R1 is furanyl (furyl), thiophenyl(thienyl) or phenylsubstituted by R11 and R12, where R11 is hydrogen, 1-4C-alkoxy,carboxyl, aminocarbonyl, halogen or di-1-4C-alkylamino and R12 ishydrogen, R2 is pyridinyl, R3 is phenyl, R4 is hydrogen, R5 is hydrogen,A1 denotes methylene and A2 denotes methylene, or a hydrate, solvate,salt, hydrate of a salt or solvate of a salt thereof.
 8. A compound offormula 1 according to claim 1, wherein R2 is 2-pyridinyl or4-pyridinyl, or a hydrate, solvate, salt, hydrate of a salt or solvateof a salt thereof.
 9. A compound of formula 1 according to claim 1,wherein R3 is phenyl, or a hydrate, solvate, salt, hydrate of a salt orsolvate of a salt thereof.
 10. A compound of formula 1 according toclaim 1, wherein R1 is furanyl (furyl), thiophenyl (thienyl) or phenylsubstituted by R11 and R12, where R11 is hydrogen, 1-4C-alkoxy,carboxyl, aminocarbonyl, halogen or di-1-4C-alkylamino and R12 ishydrogen, or a hydrate, solvate, salt, hydrate of a salt or solvate of asalt thereof.
 11. A compound of formula 1 according to claim 1, whereinR1 is furanyl (furyl), thiophenyl (thienyl) or phenyl substituted by R11and R12, where R11 is hydrogen, 1-4C-alkoxy, halogen,di-1-4C-alkylamino, aminocarbonyl, carboxyl, 1-4C-alkylcarbonylamino,hydroxyl, 1-4C-alkylcarbonyl or together with R12 methylenedioxy orethylenedioxy and R12 is hydrogen, halogen or together with R11methylenedioxy or ethylenedioxy, or a hydrate, solvate, salt, hydrate ofa salt or solvate of a salt thereof.
 12. A compound of formula 1according to claim 1, wherein R1 is 2-furanyl or 3-furanyl, or ahydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.13. A compound of formula 1 according to claim 1, wherein R1 is2-thiophenyl or 3-thiophenyl, or a hydrate, solvate, salt, hydrate of asalt or solvate of a salt thereof.
 14. A compound of formula 1 accordingto claim 1, wherein R1 is selected from the group consisting of phenyl,4-methoxyphenyl, 4-chlorophenyl, 4-dimethylaminophenyl,4-aminocarbonylphenyl, 4-carboxyphenyl, 3-chloro-4-fluorophenyl,3-acetylaminophenyl, benzo[1,3]dioxol-5-yl, 3-hydroxyphenyl,4-hydroxyphenyl, 4-acetylphenyl, 3-acetylphenyl, 4-acetylaminophenyl,4-dimethylaminocarbonyl-phenyl and 4-aminocarbonylphenyl, or a hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof.
 15. Acompound of formula 1 according to claim 1, wherein A1 denotes methyleneand A2 denotes methylene, or a hydrate, solvate, salt, hydrate of a saltor solvate of a salt thereof.
 16. A pharmaceutical compositioncomprising a compound of the formula 1 as claimed in claim 1 and/or apharmaceutically acceptable hydrate, solvate, salt, hydrate of a salt orsolvate of a salt thereof together with a pharmaceutically acceptableexcipient and/or carrier.
 17. A method of treating a patient afflictedwith a disease or disorder, comprising the step of administering atherapeutically effective amount of a compound of the formula 1 asclaimed in claim 1 and/or a pharmaceutically acceptable hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof to saidpatient afflicted with said disease or disorder, wherein the disease ordisorder is selected from the group consisting of an acute and/orchronic airway disorder, an inflammatory or allergen-induced airwaydisorder, bronchitis, obstructive bronchitis, spastic bronchitis,allergic bronchitis, allergic asthma, bronchial asthma, emphysema,chronic obstructive pulmonary disease (COPD), a disorder which is basedon an excessive release of T-Cell derived cytokines, HIV-infection,septic shock, adult respiratory distress syndrome, graft-versus-hostreactions, acute or chronic rejection of organ or tissue allo- orxenografts, generalized inflammations in the gastrointestinal area,rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, faultyimmunological reactions in the area of the upper airways and theadjacent regions, dermatoses of the proliferative, inflammatory orallergic type, psoriasis (vulgaris), toxic and allergic contact eczema,atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus inthe anogenital area, alopecia areata, hypertrophic scars, discoid lupuserythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, other proliferative, inflammatory,allergic skin disorders, a disorder in connection with disturbances ofbrain metabolism, disorders of the central nervous system (CNS),cerebral senility, senile dementia, multiinfarct dementia, depression,arteriosclerotic dementia, cancer and diabetes insipidus.
 18. A methodaccording to claim 17, in which a compound of claim 1 and/or a hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof, is usedin combination with other therapeutic agents used in clinical practicefor the treatment of the said disease or disorder.
 19. A process forpreparing a compound of formula 1 as claimed in claim 1 or a hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof, whichcomprises reacting a boronic acid derivative R1-B(OH)₂ wherein R1 hasthe meaning specified in claim 1, with a pyrimidine derivate of formula(4)

in which A1, A2, R2, R3, R4 and R5 have a meaning specified in claim 1,and optionally converting an obtained compound into a correspondinghydrate, solvate, salt, hydrate of a salt or solvate of a salt, orconverting an obtained hydrate, solvate, salt, hydrate of a salt orsolvate of a salt into a corresponding free compound.